Expanding the Phenotypic Spectrum of the Nuclear Speckleopathy SRRM2-related Neurodevelopmental Disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Nuclear speckles are membrane-less nuclear organelles that facilitate multiple dynamic RNA regulatory processes. Nuclear speckleopathies are a class of primarily neurodevelopmental genetic conditions caused by pathogenic variants in genes encoding components of the nuclear speckle. Loss-of-function variants in the SRRM2 gene, a core scaffolding protein within the nuclear speckle, were recently reported in a seminal cohort of patients with predominant neurodevelopmental delays and mild dysmorphic features. As more patients are identified via WES/WGS, we are learning more about the phenotypic spectrum, including congenital anomalies.
Methods:
We performed a retrospective chart review of three known individuals with SRRM2-related neurodevelopmental disorder seen in the Division of Genetics, Genomics and Metabolism at Lurie Children’s Hospital of Chicago (Chicago, IL). This study was approved by our local institutional review board (IRB 2023-5909). All 3 individuals included in this cohort were identified to have a de novo SRRM2 variant via trio whole exome sequencing between 2023-2024.
Results:
Individual 1 is an 8 year old male with history of developmental delay, intellectual disability (IQ 40), autism and pulmonic stenosis. Brain MRI showed relatively small cerebral volume. Physical exam was notable for mild describable features including broad nose, long smooth philtrum, thin upper lip, deep set eyes, very mild epicanthal folds and ears with squared superior helices. Previous genetics workup included chromosomal microarray and Fragile X testing which were both normal. WES revealed a de novo, pathogenic variant in SRRM2 c.5599 C>T, p.(R1867*).
Individual 2 is a 4 year old male with history of global developmental delay, non-verbal, autism, left undescended testis and inguinal hernia. Echo normal. Physical exam was notable for elevated weight, macrocephaly, prominent ears and intermittent exotropia. WES identified a de novo, pathogenic variant in SRRM2 c.657-1 G>C, p.?.
Individual 3 is a 5 year old male with history of developmental delay, attention and impulsivity issues, laryngomalacia, small anterior laryngeal glottic web, subglottic stenosis, dysphagia, GERD, mild hypotonia, right eyebrow hemangioma, hyperopia, concern for immunodeficiency and airway hyperreactivity. He underwent supraglottoplasty, tonsillectomy, adenoidectomy and ear tube placement. Echocardiogram and RBUS normal. Brain MRI showed scattered foci of T2/FLAIR hyperintensity in the bilateral cerebral white matter, potentially representing gliosis. Physical exam notable for periorbital fullness, low set ears with squared helices, mild bulbous nose, long smooth philtrum, full lips, intermittent protruding tongue and possible left inframammary supernumerary nipple. Previous genetics work up included normal microarray. Trio WES identified SRRM2 frameshift variant c.7748_7758del11, p.T2583KfsX22, initially classified as a VUS due to candidate gene status, which was then reclassified as pathogenic following seminal publication of the corresponding neurodevelopmental disorder.
Conclusion:
Our study highlights several novel features not previously reported in individuals with SRRM2-related neurodevelopmental disorder, including pulmonic stenosis, the first known congenital heart defect (CHD) to be described, cryptorchidism, inguinal hernia, laryngeal glottic web and possible immunodeficiency. These findings should prompt providers to consider echocardiogram to screen for CHD and to consider supraglottic web in a patient with unexplained respiratory distress or stridor. It is notable that the findings of pulmonic stenosis and supraglottic
web have strong genetic associations with other commonly recognized genetic diagnoses, such as Noonan syndrome and 22q11.2 deletion syndrome, respectively. Additionally, the patients included in our case series exhibited overall mild dysmorphic features that seem consistent with previously reported patients. Taken together, this highlights the power of broad genetic testing in the form of WES/WGS to diagnose these patients. Future studies will be needed to continue to refine the expanded phenotypic spectrum, including congenital anomalies, of this relatively recently described neurodevelopmental condition as well as other nuclear speckleopathies.
Nuclear speckles are membrane-less nuclear organelles that facilitate multiple dynamic RNA regulatory processes. Nuclear speckleopathies are a class of primarily neurodevelopmental genetic conditions caused by pathogenic variants in genes encoding components of the nuclear speckle. Loss-of-function variants in the SRRM2 gene, a core scaffolding protein within the nuclear speckle, were recently reported in a seminal cohort of patients with predominant neurodevelopmental delays and mild dysmorphic features. As more patients are identified via WES/WGS, we are learning more about the phenotypic spectrum, including congenital anomalies.
Methods:
We performed a retrospective chart review of three known individuals with SRRM2-related neurodevelopmental disorder seen in the Division of Genetics, Genomics and Metabolism at Lurie Children’s Hospital of Chicago (Chicago, IL). This study was approved by our local institutional review board (IRB 2023-5909). All 3 individuals included in this cohort were identified to have a de novo SRRM2 variant via trio whole exome sequencing between 2023-2024.
Results:
Individual 1 is an 8 year old male with history of developmental delay, intellectual disability (IQ 40), autism and pulmonic stenosis. Brain MRI showed relatively small cerebral volume. Physical exam was notable for mild describable features including broad nose, long smooth philtrum, thin upper lip, deep set eyes, very mild epicanthal folds and ears with squared superior helices. Previous genetics workup included chromosomal microarray and Fragile X testing which were both normal. WES revealed a de novo, pathogenic variant in SRRM2 c.5599 C>T, p.(R1867*).
Individual 2 is a 4 year old male with history of global developmental delay, non-verbal, autism, left undescended testis and inguinal hernia. Echo normal. Physical exam was notable for elevated weight, macrocephaly, prominent ears and intermittent exotropia. WES identified a de novo, pathogenic variant in SRRM2 c.657-1 G>C, p.?.
Individual 3 is a 5 year old male with history of developmental delay, attention and impulsivity issues, laryngomalacia, small anterior laryngeal glottic web, subglottic stenosis, dysphagia, GERD, mild hypotonia, right eyebrow hemangioma, hyperopia, concern for immunodeficiency and airway hyperreactivity. He underwent supraglottoplasty, tonsillectomy, adenoidectomy and ear tube placement. Echocardiogram and RBUS normal. Brain MRI showed scattered foci of T2/FLAIR hyperintensity in the bilateral cerebral white matter, potentially representing gliosis. Physical exam notable for periorbital fullness, low set ears with squared helices, mild bulbous nose, long smooth philtrum, full lips, intermittent protruding tongue and possible left inframammary supernumerary nipple. Previous genetics work up included normal microarray. Trio WES identified SRRM2 frameshift variant c.7748_7758del11, p.T2583KfsX22, initially classified as a VUS due to candidate gene status, which was then reclassified as pathogenic following seminal publication of the corresponding neurodevelopmental disorder.
Conclusion:
Our study highlights several novel features not previously reported in individuals with SRRM2-related neurodevelopmental disorder, including pulmonic stenosis, the first known congenital heart defect (CHD) to be described, cryptorchidism, inguinal hernia, laryngeal glottic web and possible immunodeficiency. These findings should prompt providers to consider echocardiogram to screen for CHD and to consider supraglottic web in a patient with unexplained respiratory distress or stridor. It is notable that the findings of pulmonic stenosis and supraglottic
web have strong genetic associations with other commonly recognized genetic diagnoses, such as Noonan syndrome and 22q11.2 deletion syndrome, respectively. Additionally, the patients included in our case series exhibited overall mild dysmorphic features that seem consistent with previously reported patients. Taken together, this highlights the power of broad genetic testing in the form of WES/WGS to diagnose these patients. Future studies will be needed to continue to refine the expanded phenotypic spectrum, including congenital anomalies, of this relatively recently described neurodevelopmental condition as well as other nuclear speckleopathies.